Mutual Prodrug
H3C
OPO3Na2
H3C
OH
Sodium phosphate
and
Carbon dioxide
O
Cl
N
Cl
O
Estermustine Sodium Phosphate
Emcyt® - Pharmacia & Upjohn
HO
Cl
NH
NH+Cl-
Aziridine
Cl
Nornitrogen mustard
Cl
Actual alkylating species
• Used for metastatic carcinoma of the prostate
• Promoiety also a drug!
• Prodrug is selectively taken up into estrogen receptor positive cells then
urethane linkage is hydroylzed
• 17-alphaestradiol slow prostate cell growth
• Nornitrogen mustard is a weak alkylating agent
Functional Groups in Prodrugs
• Carboxylic acids and Alcohols: Most common type of prodrug
O
O
Drug
O
Promoiety
Drug
HO Promoiety
+
OH
or
O
Promoiety
O
O
Drug
Promoiety
OH
+
HO Drug
• Types of esterase enzymes mediating the hydrolysis process
• Ester hydrolase, Lipases, Cholesterol esterases, Acetylcholinesterase,
Carboxypeptidase, Cholinesterase
• Bacterial microflora enzymes
• Wide number of choices of promoiety alcohols available
• Steric, electronic and hydrophobicity properties allow rate and extent of
hydrolysis to be controlled
Functional Groups in Prodrugs
H3C
NH(CH3)2+-SO4
CH3 O
O
H3C
HO
HO
H3C
O
HO
O
CH3
CH3
O
O
O
CH3
O
CH3
OMe
CH3
O
H3C
CH3
OH
Erthromycin estolate
Ilosone® - Eli Lilly
caps,tabs, suspension
Antibiotic used to treat
upper and lower respiratory
infections (URI or LRI),
Legionnaire's disease,
skin infections
• Erythromycin is a very bitter substance easily destroyed at acidic pH
• Propionate ester is to increase lipid solubility for improved absorption
• Ester must be hydrolyzed for antibacterial activity
• Lauryl sulfate salt – absorption not affected by food, less bitter after
taste and is acid stable
Esters Failure as Prodrugs
H
N
R1
O
H
S
N
O
CH3
CH3
CO2R2
R2 = ethyl, propyl, butyl, phenyl
Penicillin esters
Esterases
NO REACTION!
H
N
R1
O
H
S
N
R3
O
CO2R2
R2 = ethyl, propyl, butyl, phenyl
Cephalosporin esters
Why?
b-Lactam prodrug – Double
esters
OMe
Increase
absorption
H
N
N
H2N
Vantin® – Pharmacia & Upjohn
S
H
O
S
N
URI, UTI, Gonorrhea, skin
infections
OMe
O
Avoid acid
catalyzed
decomposition
O
Esterase
O
OMe
H
N
N
H2N
S
O
H
CH3
Taking with food
O
O
CH3
CH3
increases absorption
O
CH3
HO-Esterase
S
N
H 2O
OMe
O
O
O
H3C
CH3
CO2
+
CH3
HO
CH3
O H
OMe
H
N
N
H2N
S
O
H
S
N
OMe
O
Active Drug
O
O
+
CH3
O
CH3